Sorbitan monostearate, ethoxylated

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using Osborne Mendel rats. The test chemical was mixed with feed at dose level of0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day) for 2 years. During the study, the animals were observed for mortality, morbidity, clinical signs, boody weight and organ weight changes, hematology, gross pathology and histopathology. Survival was unaltered by chemical treatment. Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level. Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on the test chemical was statistically significant only at the 12-week period. Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency. Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups. Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages. With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g). Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically. Based on the observations made, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.

Repeated dose toxicty: Inhalation

Sorbitan monostearate, ethoxylated (CAS no 9005-67-8) has very low vapor pressure (1.919E-18 Paat 25˚C), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value forSorbitan monostearate, ethoxylated (CAS no 9005-67-8) (as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from peer reviewed publication

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

Details on test animal
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 40-50 g
- Fasting period before study:
- Housing: No data
- Diet (e.g. ad libitum): Ground commercial rat biscuits ad libitum
- Water (e.g. ad libitum): Water ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%):No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

IN-LIFE DATES: From: To: No data

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other: Feed

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose level 0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)

DIET PREPARATION
- Rate of preparation of diet (frequency): All diets were prepared in quantities approximating a 2-week supply
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water):Feed
- Concentration in vehicle: 0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years

Frequency of treatment:

Daily

Remarks:

0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day)

No. of animals per sex per dose:

0 mg/Kg/day: 12 males and 12 females
1000 mg/Kg/day: 12 males and 12 females
2500 mg/Kg/day: 12 males and 12 females
5000 mg/Kg/day: 12 males and 12 females
12500 mg/Kg/day: 12 males and 12 females

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Frequently
- Cage side observations checked in table [No.?] were included. General physical condition and abnormalities, Moribund state of animals was also noted

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Twice during the test period
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals/group
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: No data
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, Organ weights and gross pathology
were recorded for all sacrificed animal

HISTOPATHOLOGY: Yes, organs and tissues were fixed in formalin solution for histopathologic study

Other examinations:

No data

Statistics:

No data

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level.

Mortality:

no mortality observed

Description (incidence):

No effects were noted on survival of animals

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on test chemical was statistically significant only at the 12-week period.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency.

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups.

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g).

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Critical effects observed:

not specified

Table: Survival rate of rats treated for 2 years

No. of animals	Dietary level (%)	No .of survivors	Survival rate (%)
24	0	12	50.0
24	2	15	62.5
24	5	14	58.3
24	10	12	50.0
24	25	9	37.5

 

Table: Food Efficiency Of Diets Containing 25% Stearate Emulsifiers Fed To Rats For 12 Weeks

Dose level (%)	No. of animals	Sex	Average gain weight (g)	Average food intake (g)	Food efficiency (g et gain/100 g food)
0	12	M	313.2±15.3	1752	17.8
	12	F	178.6±9.8	1269	14.1
25	12	M	271.6±6.3	1589	17.1
	12	F	175.7±5.1	1485	11.9

 

Conclusions:

The no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.

Executive summary:

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using Osborne Mendel rats. The test chemical was mixed with feed at dose level of0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day) for 2 years. During the study, the animals were observed for mortality, morbidity, clinical signs, boody weight and organ weight changes, hematology, gross pathology and histopathology. Survival was unaltered by chemical treatment.Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level. Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on the test chemical was statistically significant only at the 12-week period. Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency. Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups. Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages. With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g). Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically. Based on the observations made, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from peer reviewed publication

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation, other

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: dermal, other

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data available for the target chemical was reviewed to determine its toxic nature. The studies are as mentioned below:

Repeated dose toxicity: Oral

Repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using Osborne Mendel rats. The test chemical was mixed with feed at dose level of0, 2, 5, 10, and 25% (0, 1000, 2500, 5000 or 12500 mg/Kg/day) for 2 years. During the study, the animals were observed for mortality, morbidity, clinical signs, boody weight and organ weight changes, hematology, gross pathology and histopathology. Survival was unaltered by chemical treatment. Diarrhea was apparent throughout life in rats fed the test chemical, severe at 25%, moderate at 10%, and slight at 5%. No diarrhea was notes at 2% dose level. Average weight gain was calculated after 12 weeks on the diets to measure the effect on the early and rapid growth, and again after one year on the diet. Significant growth depression occurred in some groups at the 25% feeding level but in none at 10% or below. Adverse effects were more pronounced in males than in females. The inferior weight gain shown by male rats on the test chemical was statistically significant only at the 12-week period. Early growth depression in males fed 25% of the test chemical was accompanied by reduced food efficiency. Hematology studies showed normal values for hemoglobin, red and white blood cells, and differential counts for all groups. Most animals on the highest emulsifier dosage had livers which were enlarged and more friable than normal. No significant liver enlargement occurred in rats at lower dosages. With the test chemical treatment, cecal enlargement was moderate at the 25% level and to a lesser degree at the 10% level. The increased size of the cecum was obvious at autopsy and the weight of the wall also proved to be greater for the test animals (mean of four representative ceca at the 25% level was 5.29 g) than for the controls (mean 3.59 g). Increased hepatic cell vacuolation at 25% was less-not enough to be a distinct difference. With the test chemical, the enlarged ceca were normal microscopically. Based on the observations made, the no observed adverse effect level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female rats were exposed for 2 years.

In another study, repeated dose oral toxicity study was performed to determine the toxic nature of the test chemical. The study was performed using male C57BL/6 Jax mice. The test chemical was mixed with feed and used at dose level of 0, 5 or 10% (0, 1000 or 2500 mg/Kg/day). The study was specially designed to determine the hematologic picture of the test chemical treatment. During the study, the test animals were observed for clinical signs and hematology. There were no apparent deleterious effects of any experimental diet upon life-span or general health. However, mice fed 10% concentrations produced very soft stools, and during early months of observation, developed an inflammation in the anal region.Throughout the 22 month feeding period PSMS-10% diet mice maintained the soft, shiny coat typical of young adults of this strain. HB, HMT, and RBC exhibited a marked decrease through 18 months. MCV, MCH, and MCHC did not show this pronounced decrease. Quadratic regression was significant for HB, HMT, and RBC. MCV and MCH exhibited significant negative linear regression, while MCHC regression fittings were not significant. 5% diet produced a deviation from control hematologic picture, although no morphologic anemia was evident during the study. All measurements declined precipitously during the first 10 months at 10% diet. Inexplicable increases at 14 months may indicate a temporary tolerance response to diet effect. HB, HMT, RBC, MCH, and MCHC exhibited considerably lower values at 10, 14, 18, and 22 months than controls did at any examination. However, no morphologic anemia was present, although a slight hypochromasia was evident at 10 months. 10% diet mice regressions differed from control regressions except for HMT and MCV. However, HMT quadratic regression was of a structure indicating a greater rate and magnitude of decrease at earlier ages than did control quadratic regression. Calculated means for 10% diet mice were significantly (P < 0.05) lower than control means, except for MCV. Apparently, decreased hematologic values in male C57BL/6 Jax mice is one facet of the aging process. The test chmical fed at 5% and 10% concentrations, produced a change in the normal hematologic aging pattern. Decreased hematologic values were induced at an earlier age and to a greater degree in experimental diet groups, although not to the extent of producing a morphologic anemia. Hence the no observed adverse effect level (NOAEL) for the test chemical is considered to be 5000 mg/Kg/day when male and female rats were exposed for 22 months.

Repeated dose toxicty: Inhalation

Sorbitan monostearate, ethoxylated (CAS no 9005-67-8) has very low vapor pressure (1.919E-18 Paat 25˚C), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value forSorbitan monostearate, ethoxylated (CAS no 9005-67-8) (as provided in section 7.2.3) is >2000 mg/kg body weight. Considering this, the end point for repeated dermal toxicity is considered as waiver.

Based on the data available, the test chemical is not likely to classify as a toxicant upon repeated exposure by oral, inhalation and dermal route of exposure as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available, the test chemical is not likely to classify as a toxicant upon repeated exposure by oral, inhalation and dermal route of exposure as per the criteria mentioned in CLP regulation.